Pericytes are essential cells of the neurovascular unit. They are embedded within the vascular membrane of brain capillaries making direct focal contacts with the endothelium. The existence and role of pericytes has been neglected for a long time. Interactions between endothelial cells and pericytes are important for normal functions of the capillary vessel wall. In the embryonic CNS, pericytes play a key role in the development of the microcirculation. Still, the field is at the beginning of a journey to fully understand and appreciate the biology of brain pericytes and its implications for neurological disorders. The major goals of the proposed research are to determine how pericyte deficiency in the adult and the aging brain affects key neurovascular functions and neuronal structure and function. Our central hypothesis is that pericytes maintain critical neurovascular functions which are essential for normal brain performance. We hypothesize that pericyte loss in the adult brain leads to a progressive age-dependent vascular damage by two parallel pathways: (1) reductions in brain microcirculation causing diminished capillary perfusion, reduced local CBF and hypoxic tissue damage; and (2) BBB disruption leading to brain accumulation of several neurotoxic and vasculotoxic macromolecules. We next hypothesize that pericyte loss from the adult brain leads to microvascular degeneration and vascular-mediated secondary neurodegenerative changes followed by a general inflammatory response. To test our hypothesis we propose to use 3 models of cerebrovascular hypoplasia mediated by (1) an inherited embryonic loss of CNS pericytes and PDGFR global deficiency (i.e., F7 mutants), (2) an inducible pericyte loss in the adult CNS with intact signaling pathways in pericytes (i.e., NG2-Cre;PdgfrDTR mice) and (3) a primary cerebral endothelial hypoplasia in which pericytes remain intact (i.e., Meox2+/- mice) as a non-pericyte deficiency hypoplasia model with genetically intact PDGFR signaling. Several state-of-the art techniques will be used including in vivo multiphoton microscopy, high resolution confocal microscopy, quantitative autoradiography, mathematical modeling of CBF and BBB permeability, methods to study neuronal structure and function (e.g., electrophysiology), behavioral tests and neuroinflammation. The proposed application will fill in the gap of our knowledge regarding the role of pericytes in the CNS and will likely have important implications for our understanding of a neurodegenerative process and treatment of it. We expect to generate definitive data showing that pericytes control key neurovascular functions necessary for normal structure and function of neurons and that loss of pericytes from the adult CNS has a key role in the development of microvascular and neuronal degeneration. This data should establish brain pericytes as a major new therapeutic target for neurodegenerative disorders.